U.S. patent number 11,433,234 [Application Number 16/614,397] was granted by the patent office on 2022-09-06 for external trigeminal nerve stimulation for the acute non-invasive treatment of migraine attacks.
This patent grant is currently assigned to Cefaly Technology SPRL. The grantee listed for this patent is CEFALY Technology sprl. Invention is credited to Pierre Rigaux.
United States Patent |
11,433,234 |
Rigaux |
September 6, 2022 |
External trigeminal nerve stimulation for the acute non-invasive
treatment of migraine attacks
Abstract
The current invention concerns a system and a method for the
acute non-invasive treatment of a migraine attack. The system
comprises at least one skin electrode for placement on the forehead
of a patient. The system is configured for providing consecutive
biphasic electrical pulses via said at least one skin electrode to
the supratrochlear and supraorbital nerves of the ophthalmic branch
of the trigeminal nerve during a prolonged time span. Preferably,
the time span is at least 10 minutes.
Inventors: |
Rigaux; Pierre (Liege,
BE) |
Applicant: |
Name |
City |
State |
Country |
Type |
CEFALY Technology sprl |
Seraing |
N/A |
BE |
|
|
Assignee: |
Cefaly Technology SPRL
(N/A)
|
Family
ID: |
1000006542978 |
Appl.
No.: |
16/614,397 |
Filed: |
May 16, 2018 |
PCT
Filed: |
May 16, 2018 |
PCT No.: |
PCT/EP2018/062779 |
371(c)(1),(2),(4) Date: |
November 18, 2019 |
PCT
Pub. No.: |
WO2018/210949 |
PCT
Pub. Date: |
November 22, 2018 |
Prior Publication Data
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|
|
Document
Identifier |
Publication Date |
|
US 20200179689 A1 |
Jun 11, 2020 |
|
Foreign Application Priority Data
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|
|
|
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May 19, 2017 [EP] |
|
|
17171961 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N
1/0492 (20130101); A61N 1/36021 (20130101); A61N
1/36034 (20170801); A61N 1/0496 (20130101); A61N
1/0456 (20130101); A61N 1/36025 (20130101) |
Current International
Class: |
A61N
1/36 (20060101); A61N 1/04 (20060101) |
References Cited
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|
Primary Examiner: Alter; Alyssa M
Attorney, Agent or Firm: Cooley LLP
Claims
The invention claimed is:
1. A system for the acute non-invasive treatment of a migraine
attack of a patient, the system comprising: at least one skin
electrode configured for placement on a forehead of the patient,
wherein the system is configured to provide consecutive biphasic
electrical pulses via the at least one skin electrode for a
prolonged time span, the prolonged time span is at least 10
minutes, wherein the system is configured for providing the
consecutive biphasic electrical pulses at a frequency of at least
60 Hz and at most 300 Hz, each of the consecutive biphasic
electrical pulses comprises a width of at least 30 microseconds and
at most 1000 microseconds, and wherein the system is configured for
linearly increasing the amplitude of the consecutive biphasic
electrical pulses during a first portion of the time span up to a
preconfigured upper amplitude that is maintained during a second
subsequent portion of the time span, the preconfigured upper
amplitude is at least 1 mA and at most 50 mA.
2. The system of claim 1, wherein the biphasic electrical pulses
are approximately rectangular biphasic symmetrical pulses with a
zero electrical mean.
3. The system of claim 1, wherein the time span is at least 25
minutes.
4. The system of claim 1, wherein the time span is at least 45
minutes.
5. The system of claim 1, wherein the system is configured to
provide the consecutive biphasic electrical pulses at a frequency
of at least 80 Hz and at most 300 Hz.
6. The system of claim 1, wherein the system is configured to
provide the consecutive biphasic electrical pulses at a frequency
of about 100 Hz, wherein about encompasses variations of +/-20% or
less of and from the specified value.
7. The system of claim 1, wherein each of the consecutive biphasic
electrical pulses comprises a width of about 250 microseconds
wherein about encompass variations of +/-20% or less of and from
the specified value.
8. The system of claim 1, wherein the preconfigured upper amplitude
is at least 6 mA and at most 50 mA.
9. The system of claim 1, wherein the preconfigured upper amplitude
is about 16 mA, wherein about encompass variations of +/-20% or
less of and from the specified value.
10. The system of claim 1, wherein the first portion of the time
span is at least 1 minute and at most 30 minutes.
11. The system of claim 1, wherein the first portion of the time
span is about 14 minutes, wherein about encompasses variations of
+/-20% or less of and from the specified value.
12. The system of claim 1, wherein the linear amplitude increase
during the first portion of the time span comprises a slope of at
least 1.6 .mu.A/s and at most 833 .mu.A/s.
13. The system of claim 1, wherein the linear amplitude increase
during the first portion of the time span comprises a slope of at
least 8 .mu.A/s and at most 83 .mu.A/s.
14. The system of claim 1 further comprising a patient-pushable
button, wherein, upon pushing the button during the time span, the
system is configured to maintain the provided biphasic pulse
amplitude at or prior to the time of the pushing of the button
throughout the remainder of the time span.
15. The system of claim 1, wherein the at least one skin electrode
comprises a bipolar self-adhesive electrode.
16. The system of claim 1, wherein the at least one skin electrode
is configured to stimulate the supratrochlear and supraorbital
nerves of the ophthalmic branch of the trigeminal nerve of the
patient, and wherein the system is configured for transcutaneous
transmission of consecutive biphasic electrical pulses via the at
least one skin electrode to the supratrochlear and supraorbital
nerves of the ophthalmic branch of the trigeminal nerve of the
patient for the prolonged time span.
17. The system of claim 1 further comprising a power-providing
device configured to receive at least one battery, the
power-providing device having two metallic contacts that are
positioned in electrical contact with the at least one skin
electrode, and wherein the power-providing device is configured to
be placed in stable contact with the at least one skin electrode
such that the system with the power-providing device and the at
least one skin electrode is portable.
18. A method for the acute non-invasive treatment of a migraine
attack of a patient, the method comprising: transcutaneously
transmitting consecutive biphasic electrical pulses to the
supratrochlear and supraorbital nerves of the ophthalmic branch of
the trigeminal nerve of the patient, the consecutive biphasic
electrical pulses having a frequency of at least 10 Hz and at most
300 Hz, each of the consecutive biphasic electrical pulses having a
width of at least 30 microseconds and at most 1000 microseconds,
the consecutive biphasic electrical pulses having a prolonged time
span of at least 10 minutes, the consecutive biphasic electrical
pulses having a linear amplitude increase during a first portion of
the time span up to a preconfigured upper amplitude that is
maintained during a second subsequent portion of the time span, and
the preconfigured upper amplitude is at least 1 mA and at most 50
mA.
19. The method of claim 18 further comprising: placing at least one
skin electrode on a forehead of the patient, wherein the at least
one skin electrode comprises a bipolar self-adhesive electrode; and
providing the consecutive biphasic electrical pulses via the at
least one skin electrode to the supratrochlear and the supraorbital
nerves for the prolonged time span.
Description
This application claims the benefit of European Application No.
17171961.0 filed May 19, 2017 and PCT/EP2018/062779 filed May 16,
2018, International Publication No. WO2018/210949 A1, which are
hereby incorporated by reference in their entirety as if fully set
forth herein.
TECHNICAL FIELD
The current invention concerns a system and a method for the acute
non-invasive treatment of a migraine attack. The system comprises
at least one skin electrode for placement on the forehead of a
patient. The system is configured for providing consecutive
biphasic electrical pulses via said at least one skin electrode to
the supratrochlear and supraorbital nerves of the ophthalmic branch
of the trigeminal nerve during a prolonged time span.
BACKGROUND
Migraine is a common neurobiological disorder characterized by
recurrent episodes of headache accompanied by sensory
hypersensitivity, which can significantly impair quality of life.
Acute treatments are used during a migraine attack with the
objective to abort or reduce headache pain and restore normal
function, while preventive treatments are intended to reduce attack
frequency and severity.
Current acute migraine treatments are primarily pharmacologic
approaches, with the most commonly used medications being
analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) and
triptans. These drugs bear several contraindications and are
associated with moderate to severe side effects. In patients with
frequent and/or prolonged migraine attacks, excessive consumption
of acute migraine drugs may lead to headache chronification and
medication overuse headache, which portends a worse outcome.
Moreover, some patients (particularly those with chronic migraine)
may become resistant to conventional migraine medications and thus
do not achieve sufficient pain relief. Medication-related adverse
effects and limited effectiveness highlight the need for
non-pharmacologic therapies.
Recent studies suggest that neurostimulation may be a promising
modality for the treatment of headache disorders. Several
neuromodulation technics have been investigated for the treatment
of primary headaches. Pain Physician 11(2), 187-200 (2008)
discloses open trials wherein percutaneous occipital nerve
stimulation (p-ONS) was effective for chronic migraine. Lancet
Neurology 6(4), 314-321 (2007) discloses the effectiveness of p-ONS
for chronic cluster headache. Cephalalgia 31(3), 271-285 (2011)
discloses positive results for p-ONS in a controlled study for
chronic migraine. Cephalalgia 30(3), 260-271 (2010) discloses that
a combined occipital nerve and supraorbital nerve neurostimulation
shows better efficacy than occipital nerve stimulation alone.
Neuromodulation 19(5), 507-514 (2016) discloses that while patient
functional status is improved in the perioperative period, it waned
over the long-term follow-up. Cephalalgia 33(10), 816-830 (2013)
discloses that sphenopalatine ganglion stimulation (SPG) yields
positive results in several trials mainly for the treatment of
cluster headache. However, although generally well tolerated, these
invasive neuromodulation technics could be appropriate for
intractable migraine and chronic cluster headaches, but may not be
acceptable for less severe migraine patient categories. Cephalalgia
36(6), 534-546 (2016) discloses that non-invasive vagus nerve
stimulation shows clinical benefits beyond those with standard of
care for cluster headache. However, the Journal of Headache and
Pain 16, 63 (2015) and Neurology 87(5), 529-538 (2016) report
negative results for non-invasive vagus nerve stimulation from
sham-controlled trials for chronic migraine.
BMC Neurology 11, 135 (2011) discloses a double-blind,
sham-controlled, cross-over study with healthy subjects in which
transcutaneous supraorbital neurostimulation was found to produce a
sedative effect. Neurology 80(8), 697-704 (2013) discloses a
subsequent multi-center, randomized, double-blind, sham-controlled
trial which reveals the efficacy and safety of external trigeminal
nerve stimulation (e-TNS) for the prevention of episodic migraine.
The Journal of Headache and Pain 16, 69 (2015) discloses a larger
open randomized trial in which the therapeutic efficacy in migraine
prevention was corroborated. The Journal of Headache and Pain 14,
95 (2013) discloses a prospective study of 2313 patients in which
safety and patient satisfaction have been further confirmed.
However, there remains a need in the art for a safe non-drug and
non-invasive acute treatment for migraine attacks.
US 2009/0 210 028 discloses a device for the electrotherapeutic
treatment of headaches such as tension headaches and migraines. An
electrode support has a shape and is size selected so as to allow,
independently from the subject, the excitation of the afferent
paths of the supratrochlear and supraorbital nerves of the
ophthalmic branch of the trigeminal nerve. An electrical circuit
includes a programmable signal generator suitable for creating
pulses of a duration of between 150 and 450 has with a maximum
increase in intensity of 0 to 20 mA at a rate of less than or equal
to 40 .mu.A/s and with a step up in intensity not exceeding 50
.mu.A.
US 2009/0 210 028 does not disclose the use of the device for the
acute treatment of migraine attacks. In addition, US 2009/0 210 028
does not disclose particular treatment durations.
US 2010/0 274 327 discloses an electrotherapy system for
stimulating sensory nerves within skin tissue. The system comprises
an electrode carrier, a pulse generator, an array of
skin-penetrating electrodes and surface skin electrodes, a pulse
conditioning circuit, and a power source. The system administers
biphasic pulsed current at the surface skin electrodes and
monophasic pulsed current at each skin-penetrating electrode. The
document in particular discloses the combined use of the
skin-penetrating and surface skin electrodes. The embodiments
disclosed in US 2010/0 274 327 provide an applicable electrode
patch combining both the surface skin electrodes and
skin-penetrating electrodes within this same patch. Non-invasive
treatment is not possible with such an electrode patch. The system
and in particular the surface skin electrodes are configured for
masking pain due to stimulation via the skin-penetrating
electrodes. The document does not disclose the treatment of
migraine. The document also does not disclose the ophthalmic branch
of the trigeminal nerve.
The present invention aims to resolve at least some of the problems
mentioned above.
SUMMARY OF THE INVENTION
In a first aspect, the present invention provides a system for the
acute non-invasive treatment of a migraine attack of a patient, as
disclosed in claim 1.
In a second aspect, the present invention provides a method for the
acute non-invasive treatment of a migraine attack of a patient, as
disclosed in claim 15.
The present invention is advantageous as it provides a safe
non-drug and non-invasive acute treatment method and system for
migraine attacks, and thereby fills in a long felt need in the art.
The invention is based on three clinical trials which are disclosed
in the examples.
DESCRIPTION OF FIGURES
FIG. 1 shows a timeline of a prospective clinical trial.
FIG. 2A shows a bipolar self-adhesive electrode attached to a
forehead of a patient, on which a power providing device can be
placed, as shown in FIGS. 2B and 2C.
FIG. 2D shows an alternative bipolar self-adhesive electrode
attached to a forehead of a patient.
FIG. 3 shows the time evolution of a mean pain intensity in a
prospective clinical trial.
FIG. 4 shows a power-providing device.
FIG. 5 shows a bipolar self-adhesive electrode.
FIG. 6 shows an alternative bipolar self-adhesive electrode.
FIG. 7 shows a power-providing device attached to the bipolar
self-adhesive electrode shown in FIG. 6.
FIG. 8 shows an overview of a clinical trial assessing the efficacy
and safety of home use of a treatment system according to the
present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention concerns a system and a method for the acute
non-invasive treatment of a migraine attack. The invention was
summarized in the corresponding section. In what follows, the
invention will be described in detail, preferred embodiments are
elucidated, and the invention is illustrated by means of
examples.
Unless otherwise defined, all terms used in disclosing the
invention, including technical and scientific terms, have the
meaning as commonly understood by one of ordinary skill in the art
to which this invention belongs. By means of further guidance, term
definitions are included to better appreciate the teaching of the
present invention.
As used herein, the following terms have the following
meanings:
"A", "an", and "the" as used herein refers to both singular and
plural referents unless the context clearly dictates otherwise. By
way of example, "a compartment" refers to one or more than one
compartment.
"About" as used herein referring to a measurable value such as a
parameter, an amount, a temporal duration, and the like, is meant
to encompass variations of +/-20% or less, preferably +/-10% or
less, more preferably +/-5% or less, even more preferably +/-1% or
less, and still more preferably +/-0.1% or less of and from the
specified value, in so far such variations are appropriate to
perform in the disclosed invention. However, it is to be understood
that the value to which the modifier "about" refers is itself also
specifically disclosed.
"Comprise", "comprising", and "comprises" and "comprised of" as
used herein are synonymous with "include", "including", "includes"
or "contain", "containing", "contains" and are inclusive or
open-ended terms that specifies the presence of what follows e.g.
component and do not exclude or preclude the presence of
additional, non-recited components, features, element, members,
steps, known in the art or disclosed therein. The recitation of
numerical ranges by endpoints includes all numbers and fractions
subsumed within that range, as well as the recited endpoints.
In a first aspect, the invention provides a system for the acute
non-invasive treatment of a migraine attack of a patient. The
system comprises at least one skin electrode. The at least one skin
electrode is configured for placement on the forehead of the
patient. The system is configured for providing consecutive
biphasic electrical pulses via said at least one skin electrode for
a prolonged time span. Preferably, said time span is at least
minutes, more preferably at least 25 minutes, even more preferably
at least 35 minutes, yet even more preferably at least 45 minutes,
and most preferably at least 55 minutes, such as a time span of 55,
60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130,
135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195,
200, 205, 210, 215, 220, 225, 230, 235, 240 minutes, or any value
above or in between.
The applicant has found that a prolonged treatment, i.e. for at
least 10 minutes and preferably at least about 60 minutes, is
beneficial for the pain relief during migraine attacks, both with
respect to immediate suppression of pain as well as prolonged pain
relief after finishing the treatment. The clinical trials disclosed
in the examples support this statement.
In a preferred embodiment, the biphasic electrical pulses are in
essence rectangular biphasic pulses with a zero electrical mean.
This is advantageous as these type of pulses are easy to generate
and require no net charge transfer to the patient.
In a preferred embodiment, the system is configured for providing
said consecutive biphasic electrical pulses at a frequency of at
least 10 Hz and at most 300 Hz, such as 10 Hz, 20 Hz, 30 Hz, 40 Hz,
50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 110 Hz, 120 Hz, 130 Hz,
140 Hz, 150 Hz, 160 Hz, 170 Hz, 180 Hz, 190 Hz, 200 Hz, 220 Hz, 240
Hz, 260 Hz, 280 Hz, 300 Hz, or any value in between.
The applicant had found that at a frequency of about 100 Hz, the
pulses are best capable of generating an analgesic effect by
exciting the trigeminal nerve, and more specifically the
supratrochlear and supraorbital nerves of the ophthalmic branch of
the trigeminal nerve, thereby relieving pain and treating the
migraine attack.
In an embodiment, the system is configured for providing said
consecutive biphasic electrical pulses at a frequency of at least
150 Hz and at most 500 Hz, such as 150 Hz, 160 Hz, 170 Hz, 180 Hz,
190 Hz, 200 Hz, 210 Hz, 220 Hz, 230 Hz, 240 Hz, 250 Hz, 260 Hz, 270
Hz, 280 Hz, 290 Hz, 300 Hz, 320 Hz, 340 Hz, 360 Hz, 380 Hz, 400 Hz,
420 Hz, 440 Hz, 460 Hz, 480 Hz, 500 Hz, or any value in between.
Preferably, in this embodiment, the system is configured for
providing said consecutive biphasic electrical pulses at a
frequency of at least 200 Hz and at most 400 Hz, more preferably at
least 240 Hz and at most 360 Hz, even more preferably at least 250
Hz and at most 350 Hz, yet even more preferably at least 260 Hz and
at most 340 Hz, with greater preference at least 275 Hz and at most
325 Hz, with a yet even greater preference at least 290 Hz and at
most 310 Hz, and most preferably about 300 Hz.
The applicant has performed preliminary tests indicating that
tripling the frequency from about 100 Hz to about 300 Hz may
improve the efficacy of the treatment further.
In a preferred embodiment, at least some, and preferably each, of
said consecutive biphasic electrical pulses comprises a width of at
least 30 .mu.s and at most 1000 .mu.s, preferably at least 100
.mu.s and at most 500 .mu.s, such as 100 .mu.s, 125 .mu.s, 150
.mu.s, 175 .mu.s, 200 .mu.s, 225 .mu.s, 250 .mu.s, 275 .mu.s, 300
.mu.s, 325 .mu.s, 350 .mu.s, 375 .mu.s, 400 .mu.s, 425 .mu.s, 450
.mu.s, 475 .mu.s, 500 .mu.s, or any value in between.
The applicant has found that pulses comprising a width of about 250
.mu.s induce a sufficient temporary charge build-up to be
sufficiently effective to excite (trigger action potentials) the
trigeminal nerve, and more specifically the supratrochlear and
supraorbital nerves of the ophthalmic branch of the trigeminal
nerve, thereby relieving pain and treating the migraine attack.
In a preferred embodiment, the system is configured for linearly
increasing the amplitude of said consecutive biphasic electrical
pulses during a first portion of said time span up to a
preconfigured upper amplitude which is maintained during a second
subsequent portion of said time span. Preferably, said
preconfigured upper amplitude is at least 1 mA and at most 50 mA,
more preferably at least 5 mA and at most 25 mA, such as 5 mA, 6
mA, 7 mA, 8 mA, 9 mA, 10 mA, 11 mA, 12 mA, 13 mA, 14 mA, 15 mA, 16
mA, 17 mA, 18 mA, 19 mA, 20 mA, 21 mA, 22 mA, 23 mA, 24, mA, 25 mA,
or any value in between. Preferably, said first portion of said
time span is at least 1 minute and at most 30 minutes, more
preferably at least 5 minutes and at most 20 minutes, such as 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 minutes, or any
value in between. Preferably, said linear amplitude increase during
said first portion of said time span comprises a slope of at least
1.6 .mu.A/s and at most 833 .mu.A/s, preferably at least 8 .mu.A/s
and at most 83 .mu.A/s, such as 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 .mu.A/s, or
any value in between. Most preferably, the amplitude is ramped up
from 0 mA to about 16 mA in about 14 minutes, the slope of the
linear amplitude increase thereby comprising a value of about 19
.mu.A/s.
The applicant has found that an amplitude of the pulses of about 16
mA allows the maximum space recruitment, i.e. excitation
(stimulation) of all nerve fibers of the supratrochlear and
supraorbital nerves, and thus poses an optimal effectiveness of the
treatment. The gentle linear ramp-up up to the preconfigured upper
amplitude is advantageous as it helps the patient to ease into the
strong preconfigured upper stimulation amplitude of 16 mA.
In a preferred embodiment, the system comprises a patient-pushable
button. The system is hereby configured upon shortly pushing of
said button during said time span for maintaining the provided
biphasic pulse amplitude at or prior to the time of said pushing of
said button throughout the reminder of said time span. This is
advantageous as it allows a patient, during the gentle ramp-up up
to the preconfigured upper amplitude, to push the button to
maintain the current or a previous amplitude during the reminder of
the treatment time. A patient can hence limit the intensity should
it become too high.
In a preferred embodiment, the system is further configured for
acceleration of the ramp-up upon continuously pushing of said
button for several seconds. This is advantageous as a patient who
is used to treatment of migraine attacks by means of the system can
get a speedier ramp-up and thus faster headache relief. By pressing
said button continuously for several seconds, the optimal and most
effective amplitude of 16 mA can be reached within 30 seconds. The
system is hereby configured to increase the amplitude rapidly while
the button is being continuously pushed. When the switch is
subsequently released, the amplitude stabilizes and remains
constant. By pressing the button again, the intensity increases
again as long as the button is pushed.
In an embodiment, the at least one skin electrode may comprise two
or more skin electrodes configured for attachment on the patient's
forehead for establishing two or more contacts for providing said
consecutive biphasic electrical pulses. In a most preferred
embodiment, the at least one skin electrode comprises a bipolar
self-adhesive electrode, comprising a self-adhesive side for skin
contact and an outer side comprising two contact areas for
establishing electrical contact with an energy-providing device.
FIG. 5 shows an embodiment of such a bipolar self-adhesive skin
electrode. It furthermore comprises a central protrusion over which
an energy-providing device can be positioned. FIG. 2A shows the
positioning of a bipolar self-adhesive skin electrode (6) on the
forehead of a patient. The bipolar self-adhesive skin electrode (6)
and its positioning are thereby adapted for stimulation of the
trigeminal nerve, which has three branches: the ophthalmic branch
(1), the maxillary branch (4), and the mandibular branch (5). This
nerve divides into two branches on the forehead: the internal
frontal (or supratrochlear) nerve (2) and the external frontal (or
supraorbital) nerve (3). The bipolar self-adhesive skin electrode
comprises in particular a shape and configuration adapted for
stimulation of the supratrochlear and supraorbital nerves of the
ophthalmic branch of the trigeminal nerve. FIG. 4 shows an
embodiment of a head-clampable device comprising two metallic
contacts (not shown) which can be positioned in electrical contact
with the two contact areas of said bipolar self-adhesive skin
electrode. The head-clampable device comprises a recess for
placement over the protrusion of the bipolar self-adhesive skin
electrode. The protrusion can thereby comprise a base connected on
one end to the outer surface of the skin electrode and ending on
the opposite end in a broader head. The recess of the
head-clampable device is preferably configured for stable placement
over said broader head. FIG. 2B illustrates the placement of the
head-clampable device (7) over the bipolar skin electrode. The
device comprises a button (8) for starting a treatment and/or for
limiting of said amplitude during said linear increase in said
first portion of said time span. The head-clampable device of FIG.
2B comprises two legs (9) to provide the clamping functionality.
Alternatively, the clamping functionality may also be realized by
an elastic band. Each of said legs also comprises a compartment for
positioning of one AAA-type battery for powering the device. The
system comprising the device and the at least one skin electrode is
thereby portable, i.e. a patient can walk around and has his/her
hands free.
An alternative embodiment of a power-providing device is shown in
FIG. 2C. The bipolar self-adhesive skin electrode comprises a
protrusion comprising a base connected on one end to the outer
surface of the skin electrode and ending on the opposite end in a
broader head. The power-providing device comprises a recess for
stable placement of the device over the head of the protrusion. As
can be seen in FIG. 2C, the device is thereby legless. The device
also comprises at least one compartment for the positioning of at
least one battery. Alternatively, the device comprises an internal
rechargeable battery. The device also comprises a button for
starting a treatment and/or for limiting of said amplitude during
said linear increase in said first portion of said time span. The
system comprising the device and the at least one skin electrode is
thereby also portable, i.e. a patient can walk around and has
his/her hands free.
In another embodiment, the at least one skin electrode comprises a
bipolar self-adhesive electrode, comprising a self-adhesive side
for skin contact and an outer side comprising two metallic contacts
for establishing electrical contact as well as attachment with an
energy-providing device. The self-adhesive side may comprise two
self-adhesive electrode regions. FIG. 6 shows an embodiment of such
a bipolar self-adhesive skin electrode. FIG. 2D shows the
positioning on a forehead of a bipolar self-adhesive skin electrode
(6) comprising two metallic contact areas (11). As before, the
bipolar self-adhesive skin electrode and its positioning are
thereby adapted for stimulation of the trigeminal nerve, and
preferably for stimulation of the supratrochlear and supraorbital
nerves of the ophthalmic branch of the trigeminal nerve. FIG. 7
shows an embodiment of a power-providing device comprising two
metallic contacts (not shown) positioned in electrical contact with
the two metallic contact areas of said bipolar self-adhesive skin
electrode. Preferably, the metallic contacts of the bipolar
self-adhesive electrode or the power-providing device are magnetic
for attachment of the power-providing device to the bipolar
self-adhesive skin electrode. The power-providing device comprises
a button for starting a treatment and/or for limiting of said
amplitude during said linear increase in said first portion of said
time span. Preferably, the system is portable, i.e. a patient can
walk around and has his/her hands free. Preferably, the
power-providing device is legless. Preferably, the power-providing
device comprises a rechargeable battery.
Preferably, the power-providing device is lightweight, more
preferably comprising a weight smaller than 100 g, such as a weight
of 12 g. Preferably, the power-providing device is compact, more
preferably comprising dimensions smaller than 80 mm.times.80
mm.times.30 mm, such as dimensions of 55 mm.times.40 mm.times.15
mm. Preferably, the bipolar self-adhesive electrode comprises a
length of in between 50 mm and 150 mm, such as a length of 94 mm.
Preferably, the bipolar self-adhesive electrode comprises a height
of in between 10 mm and 50 mm, such as a height of 30 mm.
Preferably, the bipolar self-adhesive electrode comprises
hypoallergenic gel.
In a preferred embodiment, the power-providing device comprises a
processing unit, a tangible non-transitory computer-readable
storage medium, and computer-readable instructions for storing
information about a treatment session on the storage medium. The
power-providing device may comprise a cable port or module for
wireless communication for data read-out of said stored
information. The cable port may be a USB port. The module for
wireless communication may be a Bluetooth module.
In a preferred embodiment, the system comprises a tangible
non-transitory storage medium, such as, for example, a programmable
electrical circuit, for setting and storing at least one and
preferably all of: the pulse frequency, the pulse width, the pulse
amplitude, the pulse ramp-up time or ramp-up slope for linear
increase of the amplitude, and the treatment time (i.e. the time
span).
The system of the first aspect of the invention may also be part of
a kit, whereby the kit also comprises a medication. Preferably, the
medication comprises one or more of an analgesic, a non-steroidal
anti-inflammatory drug, a triptan, a ditan, and a CGRP antagonist.
Depending on the needs of a patient, the patient may use a combined
treatment comprising the medication and the e-TNS. The combined
treatment may comprise the starting of the e-TNS treatment and the
intake of the medication at about the same time. The combined
treatment may comprise the intake of the medication during or after
the e-TNS treatment, when, for example, the e-TNS treatment alone
does not seem sufficiently effective for the patient.
In a second aspect, the invention provides a method for the acute
non-invasive treatment of a migraine attack of a patient. The
patient comprises a forehead, a supratrochlear nerve, and a
supraorbital nerve. The method comprises the steps of (a) placing
at least one skin electrode on the forehead of the patient and (b)
providing consecutive biphasic electrical pulses via said at least
one skin electrode to said supratrochlear and said supraorbital
nerves for a prolonged time span.
One of ordinary skill in the art will appreciate that all preferred
embodiments in relation to the system also pertain to the method.
Preferably, said at least one skin electrode comprises a bipolar
self-adhesive electrode, as noted above. Preferably, said time span
is at least 25 minutes. Preferably, said biphasic electrical pulses
are in essence rectangular biphasic symmetrical pulses with a zero
electrical mean. Preferably, said consecutive biphasic electrical
pulses are provided at a frequency of about 100 Hz. In an
alternative preferential embodiment, said consecutive biphasic
electrical pulses are provided at a frequency of about 300 Hz.
Preferably, each of said consecutive biphasic electrical pulses
comprising a width of about 250 .mu.s. Preferably, said consecutive
biphasic electrical pulses comprise an amplitude which increases
linearly over a first portion of said time span up to an upper
amplitude which is maintained during a second subsequent portion of
said time span, preferably said upper amplitude one of a predefined
upper amplitude of about 16 mA or a patient-determined upper
amplitude (button push) of at most 16 mA, preferably the slope of
said linear increase about 19 .mu.A/s.
The invention is further described by the following non-limiting
examples which further illustrate the invention, and are not
intended to, nor should they be interpreted to, limit the scope of
the invention.
EXAMPLES
Example 1: Prospective Clinical Trial
A monocentric, prospective, open-labelled clinical trial was
conducted at the Columbia University Headache Center (NY, USA). The
study was approved by the ethics committee at Columbia University
Medical Center (IRB-AAA09752) and registered on ClinicalTrials.gov
(identifier: NCT02411513). Written informed consent was obtained
from all patients included in the study.
Patients with migraine with or without aura were recruited at a
standard care visit or from home if they were experiencing a
migraine attack lasting for at least three hours, with pain
intensity stabilized for at least one hour and no intake of acute
migraine medications for the prior three hours. Inclusion criteria
were the following: adult patients aged 18 to 65 years with a
history of episodic or chronic migraine with or without aura,
meeting the diagnostic criteria listed in the International
Classification of Headache Disorders 3.sup.rd edition (beta
version) (ICHD-III beta, 2013) section 1, migraine
(https://www.ichd-3.org/1-migraine/) with the exception of
"complicated migraine" (i.e., hemiplegic migraine, migraine with
brainstem aura, ophthalmoplegic migraine/recurrent painful
ophthalmoplegic neuropathy, migrainous infarction), experiencing
headache localized to the frontal, retro- or peri-orbital
region(s), on one or either side. Exclusion criteria were the
following: (1) pregnancy; (2) treatment with onabotulinum toxin
(e.g., Botox, Dysport, Xeomin) to the head in the prior four
months; (3) supraorbital nerve blocks in the prior four months; (4)
diagnosis of other primary or secondary headache disorders, except
of medication overuse headache; (5) only temporal or occipital
headache location; (6) use of opioids in the preceding three
months; (7) use of abortive migraine medication within three hours
prior to enrollment; (8) intolerance to supraorbital
neurostimulation (allodynia); (9) implanted metal or electrical
devices in the head; and (10) cardiac pacemaker or implanted or
wearable defibrillator.
Patients were asked to rate their pain severity (baseline score)
using an eleven-point visual analogue scale (VAS) (from 0=no pain
to 10=maximum pain). The e-TNS device was then applied and
neurostimulation treatment was initiated with intensity increasing
over the first 14 minutes. Patients who were able to tolerate the
paresthesia sensation for the first five minutes (thus reaching a
minimum intensity of 7 mA or a minimum electrical dose of 1.75 pC
per impulse) without having to level off the intensity were
included and subsequently continued neurostimulation for the 55
remaining minutes. Those patients who were unable to tolerate the
initial test phase were not enrolled, on the basis of the allodynia
exclusion criterion (low nociceptive forehead skin threshold). At
the completion of the one-hour treatment phase, patients were asked
to rate their pain intensity (one-hour score) and again one hour
post-treatment (two-hour score). Use of rescue medications was
recorded at the two-hour mark; patients were also contacted the
following day regarding use of rescue medications within 24 hours
following the e-TNS treatment. Patients who took rescue medication
before the end of the post-treatment phase were deemed a drop-out.
The study design is illustrated in FIG. 1.
External trigeminal nerve stimulation (e-TNS) was applied via the
Cefaly.RTM. neurostimulator device (CEFALY Technology, Seraing,
Belgium) for a 60-minute treatment session. The device is a
constant current generator for a maximum skin impedance of 2.2
k.OMEGA. that delivers rectangular biphasic symmetrical pulses with
a zero electrical mean. In the current study, the device was
programmed with a pulse frequency of 100 Hz and a pulse width of
250 has; the total maximum dose of current delivered by a one-hour
treatment session is 1.284 Coulomb. The electrical impulses are
transmitted transcutaneously via a supraorbital bipolar electrode
(30 mm.times.94 mm) designed to cover and excite (trigger action
potentials) on both sides of the supratrochlearis and
supraorbitalis nerves (see FIGS. 2 and 5). The intensity increases
linearly to reach a maximum of 16 mA after 14 minutes and then
stays constant for 46 minutes. If the patient feels that the
stimulation is too strong, a single press on the device's button
will stabilize the intensity for the remainder of the session (in
this event, the patient receives a lower total current dosage).
Patients scored their pain intensity on a visual analogue scale
(VAS) with eleven levels (from 0=no pain to 10=maximum pain). Pain
level was assessed before the treatment was applied (baseline
score), after the one-hour treatment (1 h score) and at two hours
after the beginning of the treatment phase (2 h score). Rescue
medication intake was also recorded at 2 and 24 hours. Primary
outcome was the mean change in pain intensity after the one-hour
treatment, compared to baseline. Secondary outcomes were mean
change in pain intensity at two hours after the start of treatment
compared to baseline, as well as the percentage of patients not
requiring rescue medication at two and 24 hours following the
treatment.
Analyses were conducted on a modified intention-to-treat (mITT)
basis, i.e. the eligible population consisted of patients having
administered the treatment and for which there were a baseline
severity measurement. For each patient, the outcome was calculated
on all data available during each period, without any imputation of
missing data. Comparison between baseline and treatment results was
performed using the Wilcoxon Signed Rank test for paired
samples.
TABLE-US-00001 TABLE 1 patient demographic characteristics Number
of patients included 30 Age (years) 39.42 .+-. 12.49 Number of
female 24 (80.00 %) Data are expressed as number, mean .+-. SD or
number (%).
The trial was conducted from April 2015 through October 2015. In
total, 35 patients were screened. One patient was excluded due to
use of opioid medication within the prior three months and four
patients failed the nociceptive test (two patients were not able to
tolerate early stimulation and two patients were excluded due to
unintentional disconnection of the device from the electrode by the
patient during the test phase). The remaining 30 patients received
the full one-hour stimulation, with zero drop-out during the study
(see FIG. 1). Patient demographic characteristics are shown in
Table 1. No adverse events occurred, nor were any subjective
complaints reported during or within 24 hours after the
treatment.
Table 2 presents the study outcomes. There was a statistically
significant decrease in pain intensity, both after the one-hour
treatment and at two hours after treatment initiation. No patients
used rescue medication at the end of the two-hour period. Patients
were also contacted 24 hours after the treatment to report whether
they used rescue medication during that time frame. Of the 26
patients who were successfully contacted, 17 patients (65.4%) did
not use rescue medication within the 24 hours following the
treatment.
TABLE-US-00002 TABLE 2 Study outcomes Primary outcome Change in
pain intensity after 1 hour of -3.22 .+-. 2.40 treatment, compared
to baseline (p < 0.001*) Secondary outcomes Change in pain
intensity 2 hours after -2.98 .+-. 2.31 treatment initiation,
compared to baseline (p < 0.001*) Percentage of patients not
having required 100.00% rescue medication at 2 hours Percentage of
patients not having required 65.38% rescue medication within 24
hours** Supplementary results Patients reporting .gtoreq. 30% pain
relief at 1 hour 25 (83.33%) Patients reporting .gtoreq. 30% pain
relief at 2 hours 21 (70.00%) Patients reporting .gtoreq. 50% pain
relief at 1 hour 23 (76.67%) Patients reporting .gtoreq. 50% pain
relief at 2 hours 17 (56.67%) Patients reporting pain freedom at 1
hour 6 (20.00%) Patients reporting pain freedom at 2 hours 4
(13.33%) Data are expressed as mean .+-. SD, % or number (%).
*P-values were calculated using the Wilcoxon Signed Rank test for
paired samples. **Missing data for 4 patients
FIG. 3 presents the change in mean pain intensity. On average, pain
intensity was reduced from 5.63 to 2.42 after one hour of treatment
and to 2.66 at two hours. This reduction was statistically
significant in both cases (p<0.001).
As shown in Table 2, 76.7% of patients reported 50% pain relief at
one hour and 56.7% at two hours. Six patients (20.0%) reported pain
freedom at one hour, and four patients (13.3%) at two hours.
Regarding the neurostimulation intensity, 17 patients (56.7%)
tolerated the maximum intensity of 16 mA (i.e. received the full
dose of current of 1.284 Coulomb) and 13 patients (43.3%) required
the stimulation intensity to be limited at an average of 9.51 mA.
Sub-analysis comparing the group of 13 patients who limited the
current output and the group of 17 patients who received the total
electrical dose revealed a difference only in use of rescue
medication intake within 24 hours: 50% of patients receiving
partial current output used rescue medication, compared to 25% of
patients who received the full current dose. However, data were
only available for 10 and 16 patients in each group, respectively,
and the difference was not statistically significant (p=0.234).
Baseline pain scores were similar between the two groups (p=0.240):
mean score of 6.0 for the 13 patients who limited current output
during the stimulation vs. mean score of 5.4 for the 17 patients
who received the total electrical dose.
Concerning safety, no adverse events (AEs) or complaints were
reported during the trial, which confirms the high safety level of
the treatment. J. Headache Pain 14, 95 (2013) also demonstrated the
safety in a retrospective study on the prevention of episodic
migraine in 2313 patients, of whom only 4.3% reported adverse
effects (including 2.03% with intolerance to paresthesia). In our
study, 2 out of 34 patients (5.9%) were not enrolled due to failure
of the tolerance test. This higher percentage of intolerance to
paresthesia could be explained by increased allodynia during
migraine attacks. Interestingly, there was no increase in skin
irritation with the longer 60-minute session, compared to the
20-minute session used in prior studies.
With regards to efficacy, mean pain intensity was significantly
reduced by 57.0% after the one-hour treatment and by 52.8% at two
hours. The similar rate at the two time points indicates that pain
reduction is well-maintained for at least an hour after the end of
the neurostimulation. The percentage of patients not using rescue
medication was 100% after two hours and 65.4% after 24 hours. The
proportion of patients not taking rescue medication within 24 hours
in a placebo group for the acute treatment of migraine with
medication is usually reported to be around 32%, nevertheless the
populations are not the same and the treatment protocols are
different which make any comparison difficult. Therefore these
efficacy data are promising, although it should be taken into
account that the study was open-labelled and treatment in a clinic
setting may accentuate the placebo effect. On the other hand,
treatment in a clinic ensures appropriate application/use of the
device and proper collection of data. Of further consideration is
that patients were recruited at a minimum of three hours into a
migraine attack to ensure a stable baseline pain intensity;
however, it is known that acute pharmacologic treatments are more
effective when used earlier in a migraine attack. The effectiveness
of the e-TNS device even when used late in a migraine attack is
thus encouraging.
Comparison with published data for other acute migraine treatments
is limited because of differences in trial design. Nevertheless,
Cephalalgia 19(4), 232-240 (1999) reported a reduction in mean pain
VAS scores at one hour of 26.8% for diclofenac and 17.1% for
sumatriptan, compared to 57.1% for e-TNS in our study. At two
hours, mean pain score reductions were 50.5% for diclofenac, 40.0%
for sumatriptan and 52.7% with e-TNS.
Regarding rescue medication intake, Headache 55 Suppl 4, 221-235
(2015), a recent review on triptans for the acute treatment of
migraine, reported that use of rescue medication after a standard
dose triptan ranged from 20 to 34% and averaged 37% for NSAIDs,
versus 34.6% for e-TNS between 2 and 24 hours. Notwithstanding the
limitation of these comparisons due to differences in study design,
the data suggest a similarity in efficacy with respect to rescue
medication use. Again, it should be noted that the e-TNS treatment
was applied later in a migraine attack (at least 3 hours) than the
above acute migraine medications, which have shown better efficacy
when administered early into an attack.
Example 2: External Trigeminal Nerve Stimulation Device
The device is a small, portable product comprising legs, which is
meant to be worn on the forehead by attachment to a bipolar
self-adhesive electrode on the forehead (Figures 2, 4 and 5). The
electrode comprises a length of about 94 mm and a height of about
30 mm. Two 1.5V AAA batteries provide power to the device.
The device is an external cranial neurostimulator designed for
supraorbital neurostimulation (also known as external trigeminal
nerve stimulation or e-TNS). The electrode is designed in order to
cover both sides of the supratrochlearis and supraorbitalis nerves,
which are branches of the trigeminal nerve. Trigeminal nerve
stimulation induces a sedative effect on the central nervous
system. The electrical impulses generated by the device trigger
signals (action potentials) on the supratrochlear and supraorbital
nerves of trigeminal nerve. Repetitive excitation of the trigeminal
nerve is a neuromodulation of the trigeminal system.
Neuromodulation of the trigeminal system induces a sedative effect
on the central nervous system and a trigeminal nociceptive
threshold modification.
The device will preferably run sessions of about 60 minutes, during
which it generates very precise electrical impulses that permit
stimulation of the nerve fibers. The electrical impulses are
transmitted transcutaneously via the bipolar self-adhesive
electrode placed on the forehead. The device thereto comprises two
metallic contacts which can be positioned in connection with two
conductive areas on the bipolar self-adhesive electrode. The device
delivers energy in the form of rectangular biphasic pulses. The
intensity is increasing linearly to reach a maximum of about 16 mA
after about 14 minutes (and then stays constant for about 46
minutes). The pulse frequency is about 100 Hz. The pulse width is
about 250 has. The device is provided with a button, which upon
pressing the button, enables a user to stabilize the intensity if
the user feels that the intensity becomes too high.
The legs of the device can be configured for clamping around the
sides of a patient's head. The two legs may thereto each comprise a
plastic anti-slip layer. The legs of the device may in addition, or
alternatively, be configured for support on the ears of a patient's
head.
In an embodiment, the device and the electrode may be marketed
under the registered trademark Cefaly.RTM. and/or Cefaly.RTM.
Acute.
Example 3: Double-Blind Randomized Sham-Controlled Trial
The main objective of this study was to assess the efficacy and
safety of the device disclosed in example 2 as an acute treatment
of migraine attacks with or without aura (International
Classification of Headache Disorders [ICHD]-III beta (2013) section
1) in patients from 18 to 65 years old, in a multi-center,
double-blind, randomized, sham-controlled trial.
The multi-center, prospective, double-blind, randomized,
sham-controlled clinical trial was conducted in 3 investigation
sites. Eligible patients were randomized 1:1 to verum or sham
stimulation and treated with the device during a 1-hour e-TNS
treatment session at the clinic. Pain intensity was scored by the
patient using a visual analogue scale (VAS) before the treatment,
after the 1-hour treatment session, at 2-hour after the beginning
of the treatment initiation and finally at 24-hour after the
beginning of the treatment initiation. Anti-migraine rescue
medication intake was recorded during the 24 hours following the
beginning of the e-TNS treatment. During the different phases, the
investigator monitored the possible occurrence of adverse events
(AE). The primary outcome measure was the mean change of pain score
at 1-hour time point compared to baseline. Secondary outcome
measures were the mean change of pain score at 2-hour and 24-hour
time points compared to baseline, the proportion of patients not
having required anti-migraine rescue medication within the 24 hours
after the beginning of the e-TNS treatment.
One hundred and six (106) patients having a migraine attack with or
without aura were randomized and included in the intention-to-treat
(ITT) analysis. Among them, ninety-nine (99) were eligible for the
modified intention-to-treat (mITT) analysis, i.e. the randomized
patients having had the 1-hour stimulation treatment and having
given their headache pain intensity measurement at baseline and at
1-hour time points.
In terms of safety, one adverse event (nausea) occurred but this
event was minor and totally reversible (nausea resolved by itself
after 20 minutes). There was no serious adverse events (SAE), nor
were any subjective complaints or side effects reported in either
group within the 24 hours after the beginning of the treatment.
In terms of efficacy, in the ITT analysis, the primary outcome,
mean migraine pain intensity after the 1-hour e-TNS session
compared to baseline, was very significantly more reduced in the
verum group than in the sham group (-3.46.+-.2.32 versus
-1.78.+-.1.89, p<0.001; or -59% versus -30%, p<0.001). This
pain relief percentage was as well significantly reduced in the
verum group compared to the sham group at 2 hours and 24 hours. In
the mITT analysis, mean migraine pain intensity was as well very
significantly more reduced in the verum group than in the sham
group at the 1-hour (-3.83.+-.2.13 versus -1.85.+-.1.89,
p<0.001; or -65% versus -32%, p<0.001) and at the 2-hour and
24-hour time points. In addition, the percentage of pain-free
patients at the 24-hour time point was significantly higher in the
verum group compared with the sham group (32% versus 13%,
p<0.05), and 30% sustained pain relief for 24 hours was
significantly higher in the verum group compared to the sham group
(43% versus 21%, p<0.05). Anti-migraine rescue medication intake
within the 24 hours after the beginning of the treatment was not
significantly lower in the verum group.
Example 4: Acute Non-Invasive Treatment at Home
The present example focuses on the acute non-invasive treatment of
a migraine attack at an early stage of its development, at home,
and provides an overview of a mono-center, prospective, open-label,
phase-1 clinical trial.
4.1 Treatment System
The treatment system comprises a bipolar self-adhesive skin
electrode and a power-providing device as shown in FIGS. 2C, 2D, 6
and 7 and as discussed above in conjunction with FIGS. 2C, 2D, 6
and 7. The power-providing device comprises a rechargeable battery.
The power-providing device is configured to deliver rectangular
biphasic pulses at a frequency of about 100 Hz and comprising a
width of about 250 has. The power-providing device is configured to
increase the pulse intensity linearly from 0 mA to a maximum of
about 16 mA, during the initial about 14 minutes of a treatment
session, and to maintain the pulse intensity of about 16 mA
subsequently for about 106 minutes. The power-providing device
comprises a tangible non-transitory computer-readable storage
system for storing information about a treatment session.
The electrical pulses generated via the power-providing device run
through the metallic contacts of the device and the skin electrode
in order to carry out excitation on the supratrochlear and
supraorbital nerves of the trigeminal nerve. Repetitive excitation
of the trigeminal nerve is a neuromodulation of the trigeminal
system, inducing a sedative effect on the central nervous system
and a trigeminal nociceptive threshold modification, which causes
headache pain relief during migraine attacks.
4.2 Study Measures
Headache pain severity: In order to evaluate the modification of
pain severity from baseline to 2-hour and 24-hour time points,
patients were asked to note their headache pain intensity on the
following scale: grade 0=no pain; grade 1=mild pain; grade
2=moderate pain; and grade 3=severe pain. Migraine associated
symptoms: The patient also noted the presence of migraine
associated symptoms (photophobia, phonophobia, nausea, vomiting)
and specified which associated symptom is the most bothersome
symptom (MBS) at baseline. Rescue medication intake: The patient
also recorded the intake of ANY acute rescue medication during the
24 hours following the beginning of the e-TNS session.
4.3 Population Criteria
The following inclusion criteria have been applied: 1. Age from 18
to 65 years on the day of signing the informed consent form 2.
.gtoreq.1-year history of migraine with or without aura according
to the diagnostic criteria listed in ICHDIII beta (2013) section 1,
migraine (8), with the exception of aura without headache,
hemiplegic migraine and brainstem aura migraine 3. Migraine onset
before the age of 50 years 4. Having between 2 and 8 moderate or
severe migraine attacks (grade 2 or 3) per month in each of the two
months prior to screening 5. Patient understands the study
procedures, alternative treatments available, and voluntarily
agrees to participate in the study by giving written informed
consent 6. Patient is able to read and understand the written
information (instruction sheet, paper diary and AE collecting
form)
The following exclusion criteria have been applied: 1. Patient has
difficulty distinguishing his/her migraine attacks from
tension-type headaches 2. Patient has more than 15 headache days
per month 3. Patient having received supraorbital nerve blocks in
the prior 4 months 4. Patient having received Botox treatment in
the prior 4 months 5. Modification of a migraine prophylaxis
treatment in the previous 3 months 6. Diagnosis of other primary
headache disorders, except rare tension-type headaches (<4 per
month) 7. Diagnosis of secondary headache disorders included
Medication Overuse Headache 8. Patients abusing opioids or user of
recreational or illicit drugs or has had a recent history (within
the last year) of drug or alcohol abuse or dependence 9. Implanted
metallic or electronic device in the head 10. Cardiac pacemaker or
implanted or wearable defibrillator 11. Patient having had a
previous experience with a Cefaly.RTM. device 12. Migraine Aura
without headache 13. Patient is currently participating or has
participated in a study with an investigational compound or device
within 30 days of screening visit 14. Patients not having the
ability to use appropriately the treatment system and/or to perform
themselves or bear a first 20-minute stimulation session during a
training session at the study site
4.4 Study Protocol
4.4.1 Recruitment Phase
An overview of the study protocol is shown in FIG. 8. A total of 60
patients were screened. Patients were trained about the practical
use of the treatment system (oral explanation, video, and
instruction sheet) and performed themselves a first 20-minute
treatment session to check the ability to use the treatment system
appropriately. A total of 59 patients were included in the study,
as one patient failed the training test (exclusion criterion
14).
Screened patients meeting all inclusion criteria and none of the
exclusion criteria were enrolled in the trial and received the
treatment system to be used at home to treat a single migraine
attack as well as a diary and adverse effects form. The
investigator explained to the patient how to fill in these
documents.
The patient completed a practice diary for a simulated migraine
during the screening visit, to ensure that the patient comprehends
the procedure. The investigator or study coordinator then reviewed
the diary in detail with the patient.
4.4.2 Acute Treatment Phase
During the 2 months following the screening visit, the patient was
instructed to treat a single qualifying migraine headache. A
migraine headache is qualifying if all the following conditions are
met: 1. The migraine headache severity is moderate or severe (Grade
2 or 3). 2. The migraine headache is associated with at least one
of these migraine-associated symptoms: photophobia, phonophobia,
nausea, vomiting. 3. The migraine headache started less than four
hours ago or the patient woke up with migraine. 4. No other
migraine headache or headache has occurred in the previous 48
hours. 5. The migraine headache is not already resolving on its own
i.e. the pain is not already diminishing. 6. No acute anti-migraine
medication has been taken since the beginning of the migraine
headache.
In case of a qualifying migraine headache, the patient had to apply
the system for a complete treatment session of 2 hours as soon as
the migraine headache was moderate or severe (Grade 2 or 3).
In the diary, the patient noted the grade of the headache pain
severity. The patient noted as well the migraine associated
symptoms (photophobia, phonophobia, nausea, vomiting) and specified
which associated symptom was the most bothersome symptom (MBS). The
patient noted this data just before the start of the treatment and
2 hours after the beginning of the treatment session (normally just
after removing the device and the electrode if the session ran
correctly) (2-hour data), whatever the duration of the stimulation
session. The patient also had to record if any aura was associated
with the qualifying migraine attack. The patient noted as well the
migraine associated symptoms.
Patients were instructed to not take any acute anti-migraine
medication during the 2-hour acute treatment phase. Medication
intake during the 2-hour treatment phase was considered as a
protocol violation.
During the acute treatment phase, when the treatment system was
stopped, it was not allowed to be restarted. Duration, intensity
and/or interruption were recorded for each patient thanks to a
built-in electronic system in the power-providing device.
In the adverse effects form, the patient recorded any adverse
effects occurring during the treatment phase. The patients had
furthermore been instructed to notify the investigator immediately
for any serious or severe adverse experience with the
stimulation.
4.4.3 Post-Treatment Phase
Two hours after the beginning of the treatment session, the patient
was allowed to take rescue medication if the migraine headache pain
was still moderate or severe, or if after initial pain relief (no
headache or mild headache pain) a moderate or severe headache was
resuming.
The patient had to note the headache pain severity in the diary at
24 hours after the beginning of the treatment session (24-hour
data), as well as the migraine associated symptoms. Patients were
also instructed to record in their diary the rescue medication
intake, if any, during the 24 hours following the beginning of the
treatment session.
In the adverse effects form, the patient recorded any adverse
effects occurring during the 24 hours following the beginning of
the treatment session. The patients had furthermore been instructed
to notify the investigator immediately for any serious or severe
adverse experience with the stimulation.
4.4.4 Final Visit
The patient were instructed to return to the study site within
approximately 4 days after the treatment session to return the
treatment system, the diary, and the adverse effects form. The
investigator reviewed the paper diary in detail to ensure data
accuracy (to avoid any missing data, unclear data or
discrepancies).
All adverse effects reported on the adverse effects form have been
reviewed by the investigator to assess severity. Additionally, the
investigator has inquired for adverse effects not reported on the
form.
4.4.5 Patients Compliant with the Study Protocol
11 of the 59 patients were not compliant with the study protocol: 4
patients withdrew from the study; 1 patient gave no news and did
not come back; and 6 patients violated the protocol: 2 patients did
not experience a qualifying migraine during the 2-month period; 2
patients took rescue medication within the 2-hour treatment period,
and one of them also did not report the headache severity or
symptoms at 2 hours; 2 patients did not report headache severity or
symptoms at 2 hours.
A total of 48 patients completed the study and were eligible for
inclusion in the modified intention-to-treat (mITT) analysis.
The pain intensity at baseline was moderate for 68.75% of patients
and severe for 31.25% of patients.
A total of 15 patients (31.25%) experienced a migraine attack with
aura, while 33 patients (68.75%) experienced a migraine attack
without aura.
The most reported MBS at baseline was photophobia (56.25%). Nausea
and phonophobia were the second most reported MBS at baseline
(22.92% and 18.75%, respectively). Only one patient (2.08%)
reported vomiting as the MBS at baseline.
4.5 Statistical Analysis
4.5.1 Hypotheses
1. The treatment allows to achieve pain freedom, as measured by
pain freedom at 2 hours and sustained pain freedom at 24 hours. 2.
The treatment allows to achieve migraine-associated symptom
freedom, as measured by MBS freedom at 2 hours and percentage of
patients with absence of migraine-associated symptoms at 2 hours.
3. The treatment allows to achieve pain relief, as measured by pain
relief at 2 hours. 4. The treatment allows to reduce the use of
rescue medication, as measured by the use of rescue medication
between 2 and 24 hours. 5. No serious adverse effects due to 2-hour
e-TNS session with the treatment system within the 24 hours
following the beginning of the treatment.
4.5.2 Methods of Statistical Analysis
The statistical analysis was executed on a modified
intention-to-treat (mITT) basis. Patient data were included in the
mITT analysis if all the following conditions are met: 1. The
patient treated a qualifying migraine. 2. The patient applied the
treatment during at least one minute. (If the patient stopped the
2-hour treatment session before its end for any reason, he/she was
kept in the mITT analysis if all the other conditions are met.) 3.
The headache pain severity score AND the migraine associated
symptom(s) at baseline were reported in the diary. 4. The headache
pain severity score OR the migraine associated symptom(s) at 2
hours were reported in the diary.
If the patient took rescue medication between 2 hours and 24 hours
after the beginning of the e-TNS session, the headache pain
intensity and associated symptoms presence can be affected by the
medication and the last value carried forward method (2-hour value
carried forward method in this case) was applied for the 24-hour
time point headache pain severity and migraine associated
symptoms.
4.6 Outcomes
A total of 17 patients (35.42%) were pain-free at 2 hours. A total
of 29 patients (60.42%) were MBS-free at 2 hours: 5 out of the 11
patients with nausea as MSB at baseline (45.45%) were MBS-free at 2
hours; 0 out of the 1 patients with vomiting as MSB at baseline
(0.0%) were MBS-free at 2 hours; 17 out of the 27 patients with
photophobia as MSB at baseline (62.96%) were MBS-free at 2 hours; 7
out of the 9 patients with phonophobia as MSB at baseline (77.78%)
were MBS-free at 2 hours; A total of 34 patients (70.83%) achieved
pain relief at 2 hours. A total of 22 patients (45.83%) had no
migraine-associated symptom at 2 hours. Half of the patients took
rescue medication after the treatment session.
A total of 12 patients (25.00%) achieved sustained pain freedom at
24 hours.
On average, the patients used the treatment system during 111.23
minutes. A total of 42 patients used the treatment system during
the required 120 minutes.
Out of the 59 patients included in the trial, 15 patients reported
at least one adverse effect. A total of 21 adverse effects were
reported. All reported adverse effects were minor and fully
reversible (they resolved without aftereffects). The most reported
adverse effects were burning sensation on forehead (7/21) and an
itching, tingling, stinging and/or forehead numbness (5/21)
sensation on forehead. It should be noted 4 patients discontinued
from the study due to adverse effects: 3 patients due to burning
sensation on forehead and one patient due to intense tingling
sensation inside head. No serious adverse effects were reported in
the course of the trial. No adverse treatment system effect was
noted in the course of the trial.
4.7 Comparison to Drugs
The present treatment is compared to several drugs:
[A] Adhesive Dermally-Applied Microarray (ADAM) zolmitriptan (3.8
mg), data from Spierings et al., Cephalalgia 38(2), 215-224 (2018),
http://dx.doi.org/10.1177/0333102417737765 [B] Lasmiditan (400 mg),
data from Farkkila et al., The Lancet Neurology 11(5), 405-413
(2012), http://dx.doi.org/10.1016/51474-4422(12)70047-9 [C]
Sumatriptan Iontophoretic Transdermal System, data from Goldstein
et al., Headache: The Journal of Head and Face Pain 52(9),
1402-1410 (2012),
http://dx.doi.org/10.1111/j.1526-4610.2012.02198.x [D] Sumatriptan
Nasal powder (AVP-825), data from Cady et al., Headache: The
Journal of Head and Face Pain 55(1), 88-100 (2015),
http://dx.doi.org/10.1111/head.12472 [E] Transcranial magnetic
stimulation**, data from Lipton et al., The Lancet Neurology 9(4),
373-380 (2010), http://dx.doi.org/10.1016/S1474-4422(10)70054-5 [F]
Ubrogepant (100 mg), data from Voss et al., Cephalalgia 36(9),
887-898 (2016), http://dx.doi.org/10.1177/0333102416653233
An overview of the comparison is provided in table 3. The table
comprises percentages of patients.
TABLE-US-00003 TABLE 3 Comparison of the present study to drugs
Present study [A] [B] [C] [D] [E] [F] Pain freedom at 35.4% 41.5%
28% .sup. 18% 34% 39% 25.5% 2 h MBS freedom 60.4% 68.3% NA NA NA NA
NA at 2 h Pain relief at 70.8% .sup. 80% 65% 52.9% 68% 72% 58.8% 2
h Absence of 45.8% NA NA NA 19% NA NA symptoms at (1 h) 2 h Use of
rescue 50.0% NA 42% .sup. 40% 37% 48% NA medication (48 h) between
2 h and 24 h Sustained pain 25.0% 31.7% NA NA 28% 29% 21.6% freedom
at 24 h Nausea freedom 72.9% 81.7% ~26% 83.6% NA 63% 70.6% at 2h*
*** Vomiting 95.8% NA ~5% NA NA NA NA freedom at 2 h* Photophobia
62.5% 69.5% ~38% .sup. 51% NA 37% 54.9% freedom at 2 h* ***
Phonophobia 68.8% 69.5% ~30% .sup. 55% NA 47% 60.8% freedom at 2 h*
*** At least one 25.4% 51.8% 84% .sup. 50% NA 14% 29.4% treatment-
(18.6%) **** emergent adverse effect *Irrespective of MBS. **75% of
patients had no pain or mild pain at baseline. ***Values from
per-protocol data set limited to patients with moderate or severe
pain at baseline, while other values are from mITT data set. ****5%
for treatment-related adverse effects
The present treatment system allows to achieve pain freedom, as
measured by pain freedom at 2 hours. Results are better than those
reported for other acute treatments, except ADAM zolmitriptan and
transcranial magnetic stimulation. Sustained pain freedom at 24
hours associated with the present treatment system is limited due
to the high percentage of rescue medication intake, but is within
the range reported for other acute treatments (20-30%).
The present treatment system allows to achieve migraine-associated
symptom freedom, as measured by MBS freedom at 2 hours and
percentage of patients with absence of migraine-associated symptoms
at 2 hours. Results are better than those reported for other acute
treatments, except ADAM zolmitriptan.
The present treatment system allows to achieve pain relief, as
measured by pain relief at 2 hours. Results are better than those
reported for other acute treatments, except ADAM zolmitriptan and
transcranial magnetic stimulation.
The present treatment system is associated with higher rate of
rescue medication intake between 2 and 24 hours than triptans, but
is similar to the rate reported for transcranial magnetic
stimulation.
In terms of safety, the present treatment system is associated with
a highly better safety level than triptans. Compared to ADAM
zolmitriptan, that is the triptan with best efficacy results, the
number of patients with at least one adverse effect is
significantly lower for the present treatment system (18.6%,
compared to 51.8% for ADAM zolmitriptan).
Based on these findings, the present treatment system seems to have
the better efficacy/safety ratio among the currently available
abortive treatments of migraine. Knowing that many patients tend to
overuse acute anti-migraine medications, which is a major factor of
migraine chronification, this safe and efficient non-drug and
non-invasive acute anti-migraine treatment will be a progress for
the management of migraine patients.
In an embodiment, the treatment system, the bipolar self-adhesive
electrode and/or the power-providing device may be marketed under
the registered trademarks Cefaly.RTM., Cefaly.RTM. Acute, and/or
Cefaly.RTM. Abortive Program.
* * * * *
References